Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) is a rare, inherited disorder marked by a progressive decline in kidney function. It is transmitted from an affected parent, so each child has a 50% chance of inheriting the mutation. For most ADTKD genes, such as UMOD, HNF1B, REN, and SEC61A1, standard next-generation sequencing (NGS) methods are sufficient. In contrast, mutations in the MUC1 gene occur in a highly repetitive, GC-rich variable number of tandem repeats (VNTR). A common mutation is the insertion of an extra cytosine (insC) in one 60-basepair unit, which causes a frameshift and results in a toxic protein.
The complex architecture of the MUC1 VNTR makes it largely inaccessible to standard NGS, and therefore, specialized diagnostic methods are required. A snapshot assay, using probe extension, can detect the typical insC mutation, while long-read sequencing, such as SMRT sequencing, enables complete assembly of the VNTR and precise localization of mutations. These approaches are essential when clinical features, or a strong family history, raise suspicion of ADTKD, MUC1, prompting a comprehensive diagnostic workup.
VNtyper 2.0 is a screening tool that leverages standard short-read sequencing data to analyze the MUC1 gene rapidly. It democratizes diagnostics by enabling fast, high-throughput screening of large cohorts, allowing for the detection of the prototypic insC mutation and other alterations within the VNTR. However, any positive or ambiguous screening result must always be confirmed by an independent method, and when a strong clinical suspicion exists, targeted specialized diagnostics should be initiated.
Institut Imagine (VNTyper)
24 Boulevard du Montparnasse
75015 Paris, France
https://www.institutimagine.org/en
Labor Berlin – Charité Vivantes GmbH (VNTyper)
Sylter Straße 2
13353 Berlin, Germany
Email: info@laborberlin.com
Phone: +49 (30) 405 026-800
Institute of Human Genetics Erlangen
DNA analyses: Illumina short-read sequencing, immunodetection of MUC1fs in tissues
Schwabachanlage 10
91054 Erlangen, Germany
https://www.humangenetik.uk-erlangen.de
Czech Republic Diagnostic Center
DNA analyses: Illumina short-read sequencing, PacBio sequencing, VNTR length typing, immunodetection of MUC1fs in tissues and urinary cells, ELISA of MUC1(CA15-3) in plasma
Martina Živna and Stan Kmoch
Research Unit for Rare Diseases, Charles University
Building E4, 2nd floor, Ke Karlovu 2
Prague 2, 120 00, Czech Republic
https://udmp.lf1.cuni.cz/en
The diagram below outlines two diagnostic pathways.